Abstract Identification of receptors for transcytotic delivery of therapeutic agents The Blood-Brain-Barrier (BBB) is a fundamental obstacle for the development of therapeutic and diagnostic reagents/drugs for treating brain diseases such as glioma or Alzheimer?s Disease. Current approaches enhance the delivery of therapeutics to the brain utilizing receptors on the endothelial cells of the brain capillaries by targeting with monoclonal antibodies (mAbs) for transcytotic delivery of the mAb and conjugated drugs or fused proteins for therapy. The most widely studied receptors thus far for crossing the BBB are the transferrin receptor (TfR) and human insulin receptor (HIR), both of which are highly expressed by endothelial cells that make up the BBB. In this approach, mAbs conjugated to therapeutic drugs or proteins are transported from the blood into the brain parenchyma to achieve efficacy; however, systemic toxicity and low transport efficiency has hampered clinical applications. There is still a pressing need for the identification of new receptors with high transport efficiency and brain specific expression to enhance the therapeutic index. Our approach will address this barrier by identifying these receptors with a combinatorial library comprised of single-chain variable fragment (scFv) delivered by an engineered replication-competent lentivirus as a lentiviral scFv display library. In vivo selection based on this platform will provide antibodies with binding properties that are optimized for transcytosis, which cannot be achieved by in vitro selection on human cells. Success of the project, this multi-target, transcytotic platform, is anticipated to accelerate the development of new therapies for diseases of the brain. We will generate a panel of scFvs that can target different receptors capable of transcytosing a payload of chemotherapeutics, therapeutic genes, or fused protein-based agonists/antagonists to treat diseases such as glioblastoma or Alzheimer?s Disease.